Recent reports of neurologic injury occurring after spinal and epidural anesthesia highlight substantial gaps in our current understanding of local anesthetic neurotoxicity. Specifically, the mechanism of injury is unknown, the anatomic correlates ill-defined, and the factors that promote or attenuate damage, poorly understood. Despite major advances during the last decade in purification and characterization of neurotrophic factors, no specific therapy exists. The lack of a relevant experimental model has been a major barrier to study of neurotoxic damage to the spinal cord and nerve roots. Modifying well-validated techniques for intrathecal catheterization, drug delivery and sensory assessment in the rat, we have developed an in vivo model suitable for such investigation. The proposed project will use this model to delineate the structural changes underlying dysfunction, a prerequisite to applying histologic techniques to study basic mechanisms of toxicity. The proposed studies will also use this model along with established in vitro methodology to determine whether the "therapeutic index" for functional deficit and the safety margin for irreversible conduction block differ for currently used local anesthetics. The proposed studies will determine whether combinations of anesthetic interact in an additive, sub- additive or synergistic fashion. The effect of increasing duration of anesthetic exposure will be studied to determine if neurotoxicity is solely a concentration-dependent function. The proposed studies will also determine whether nerve growth factor (NGF) can minimize or eliminate damage to the central process of a primary afferent, or facilitate recovery of function. A positive finding would indicate potential for neurotrophic-based treatment of spinal cord nerve root injury. Finally, to determine whether local anesthetic neurotoxicity results from blockade of the voltage-gated sodium channel, per se, we will establish whether the neurotoxic potential of local anesthetics exceed that of tetrodotoxin, a highly selective sodium channel blocker. A positive finding would indicate that local anesthetic effect and neurotoxicity are mediated by different mechanisms and would affirm that a safer anesthetic can be developed based on the tetrodotoxin pharmacophore. The proposed project is part of a larger effort that includes ongoing clinical studies and in vitro investigations of subarachnoid anesthetic distribution directed at improving the safety and efficacy of spinal and epidural anesthesia.